CN113662920A - Bilastine orally disintegrating tablet and preparation method thereof - Google Patents
Bilastine orally disintegrating tablet and preparation method thereof Download PDFInfo
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- CN113662920A CN113662920A CN202111147024.6A CN202111147024A CN113662920A CN 113662920 A CN113662920 A CN 113662920A CN 202111147024 A CN202111147024 A CN 202111147024A CN 113662920 A CN113662920 A CN 113662920A
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- bilastine
- mannitol
- orally disintegrating
- disintegrating tablet
- tablet
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- ACCMWZWAEFYUGZ-UHFFFAOYSA-N bilastine Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1C(CC1)CCN1CCC1=CC=C(C(C)(C)C(O)=O)C=C1 ACCMWZWAEFYUGZ-UHFFFAOYSA-N 0.000 title claims abstract description 41
- 229960004314 bilastine Drugs 0.000 title claims abstract description 41
- 239000006191 orally-disintegrating tablet Substances 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 45
- 229930195725 Mannitol Natural products 0.000 claims abstract description 45
- 239000000594 mannitol Substances 0.000 claims abstract description 45
- 235000010355 mannitol Nutrition 0.000 claims abstract description 45
- 239000002245 particle Substances 0.000 claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 8
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 6
- 229920002785 Croscarmellose sodium Polymers 0.000 claims abstract description 5
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229960001681 croscarmellose sodium Drugs 0.000 claims abstract description 5
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims abstract description 5
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 5
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 5
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 23
- 239000003826 tablet Substances 0.000 claims description 19
- 239000008187 granular material Substances 0.000 claims description 14
- 238000002156 mixing Methods 0.000 claims description 7
- 239000004376 Sucralose Substances 0.000 claims description 4
- 239000011812 mixed powder Substances 0.000 claims description 4
- 235000019408 sucralose Nutrition 0.000 claims description 4
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 208000024780 Urticaria Diseases 0.000 claims description 2
- 206010039083 rhinitis Diseases 0.000 claims description 2
- 239000008188 pellet Substances 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 6
- 229960001855 mannitol Drugs 0.000 abstract description 3
- 239000000945 filler Substances 0.000 abstract description 2
- 229960003943 hypromellose Drugs 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 6
- 238000003860 storage Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 210000000214 mouth Anatomy 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000008108 microcrystalline cellulose Substances 0.000 description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000007908 dry granulation Methods 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 238000004806 packaging method and process Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000032798 delamination Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 238000013441 quality evaluation Methods 0.000 description 2
- 230000009747 swallowing Effects 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- 229940124056 Histamine H1 receptor antagonist Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000007767 bonding agent Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000001007 flame atomic emission spectroscopy Methods 0.000 description 1
- 238000005243 fluidization Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000000938 histamine H1 antagonist Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 150000003839 salts Chemical group 0.000 description 1
- 230000001932 seasonal effect Effects 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- FIAFUQMPZJWCLV-UHFFFAOYSA-N suramin Chemical compound OS(=O)(=O)C1=CC(S(O)(=O)=O)=C2C(NC(=O)C3=CC=C(C(=C3)NC(=O)C=3C=C(NC(=O)NC=4C=C(C=CC=4)C(=O)NC=4C(=CC=C(C=4)C(=O)NC=4C5=C(C=C(C=C5C(=CC=4)S(O)(=O)=O)S(O)(=O)=O)S(O)(=O)=O)C)C=CC=3)C)=CC=C(S(O)(=O)=O)C2=C1 FIAFUQMPZJWCLV-UHFFFAOYSA-N 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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Abstract
The invention discloses a bilastine orally disintegrating tablet and a preparation method thereof. The bilastine orally disintegrating tablet is mainly characterized by comprising bilastine bulk drug, mannitol, croscarmellose sodium, hypromellose and sodium stearyl fumarate, wherein the filling agent in the prescription is sheet mannitol, and the particle size is controlled within a certain range.
Description
Technical Field
The invention belongs to the field of research of pharmaceutical preparations, and particularly relates to a bilastine orally disintegrating tablet and a preparation method thereof.
Background
Bilastine is a histamine H1 receptor antagonist produced by spain FAES FARMA, a 20mg standard plain tablet was first approved for symptomatic treatment of symptomatic rhinitis (seasonal and perennial) and urticaria in germany at 9, 8 days 2010 in the european union/european economy (28 countries france, uk, etc.) and subsequently approved in 122 countries/regions of singapore, brazil, mexico, japan, etc. by 8 months 2020. However, no bilastine formulation is currently on the market in china.
The oral administration form of the conventional tablet can satisfy the needs of the conventional adult, but the large size and difficulty in swallowing for children affect the compliance of the medication, and in these people, there is a great demand for a solid preparation which can be dissolved or suspended in water, can be chewed or can be rapidly dissolved in the mouth. The orally disintegrating tablet can be rapidly disintegrated in the oral cavity under the anhydrous condition (or only a small amount of water exists), enters the digestive tract along with swallowing, is absorbed without a mucous membrane in the oral cavity, and has the same absorption and metabolic processes with the common tablet.
Bilastine orally disintegrating tablets (specification: 10mg) developed in 11/28/lunarini International Operations Luxembourg s.a. are marketed in germany for the first time, and then marketed in other countries in europe through a mutual approval procedure (hereinafter referred to as "original development agent"). The patent CN104398481A discloses a prescription and a preparation method of a bilastine orally disintegrating tablet, wherein the bilastine orally disintegrating tablet comprises 15-30% of bilastine, 35-74% of microcrystalline cellulose, 10-40% of lactose, 0-10% of a dry adhesive, 2.0-10% of a disintegrating agent and 0.4-3% of a lubricant, and the preparation process adopts a direct powder tabletting technology and a dry granulation tabletting technology.
The inventor finds that the prior art has the following problems in the implementation process:
problem 1: the original preparation has strong hygroscopicity, the disintegration time is slowed after long-term storage, and influence factor researches show that black spots appear on the surface of the tablet in the high-temperature storage process at 60 ℃.
Problem 2: the orally disintegrating tablet is required to be disintegrated in the oral cavity, so the mouthfeel is important, the dosage form is required to have no gritty feel after being disintegrated in a CDE research meeting, and the patent CN104398481A adopts microcrystalline cellulose which is a water-insoluble auxiliary material as a main filling agent and adopts dry granulation, so the obtained granules are hard and seriously affect the mouthfeel.
Problem 3: although the content uniformity of the original preparation conforms to the pharmacopeia standard, the content variation range is large, and the inventor researches show that the bilastine bulk drug and the auxiliary material are easy to delaminate again in the transfer process after being uniformly mixed, the bilastine bulk drug mainly exists in the discharging process and the tabletting vibration process, the content uniformity is poor, and the variation range of the content of each tablet is large.
Therefore, how to obtain the bilastine orally disintegrating tablet which is more stable, has better mouthfeel and better quality has important significance.
Disclosure of Invention
The invention aims to solve the problems existing in the prior art of a bilastine orally disintegrating tablet and provides a bilastine orally disintegrating tablet with better quality and a preparation method thereof. Through a large number of experimental researches, the inventor successfully solves the problems of layering, hygroscopicity and mouthfeel during storage, and obtains a bilastine orally disintegrating tablet which is more stable, better in mouthfeel and better in quality.
The invention is realized by the following technical means:
a bilastine orally disintegrating tablet comprises the following components in parts by weight:
the bilastine provided by the invention can be in a conventional form of bilastine, such as an amorphous form, a crystal form or a salt form.
The hypromellose, croscarmellose sodium, sucralose and sodium stearyl fumarate used in the invention can be obtained from the market.
The mannitol used in the invention has a sheet or spherical microstructure, and the particle size is controlled to be more than 30 mu m and less than D50＜90μm、65μm＜D90＜205μm。
The bilastine orally disintegrating tablet provided by the invention effectively solves the problems of hygroscopicity and mouthfeel during storage, and is a bilastine orally disintegrating tablet which is more stable, better in mouthfeel and better in quality.
In some preferred embodiments, the mannitol in the formulation should have a plate-like microstructure and a particle size controlled to be 48 μm < D50＜63μm、115μm＜D90< 1345 μm, for example model 50C, manufactured by Rogat, France. The inventor finds that the mannitol with the optimal specification does not generate the problems of fluidized layering and vibration layering in the production process, and the uniformity of the formed tablets has smaller variation range.
The invention also provides a preparation method of the bilastine orally disintegrating tablet, which comprises the following steps:
(1) preparing a solution with the mass concentration of 3-7% by using the hydroxypropyl methylcellulose according to the prescription amount for later use;
(2) uniformly mixing the bilastine, the mannitol, the croscarmellose sodium and the sucralose according to the prescription amount;
(3) wet granulating, drying and grading the mixed powder prepared in the step (2) by adopting the solution prepared in the step (1) to obtain dry granules;
(4) adding sodium stearyl fumarate with a prescription amount into the dry granules, and uniformly mixing to obtain intermediate granules;
(5) and (4) tabletting the intermediate granules obtained in the step (4).
In some embodiments, step (5) tableting uses an 8mm circular punch.
In some embodiments, the tablet hardness of step (5) is controlled to 3 to 6 kgf.
According to the method, the tablets formed after tabletting can be subjected to conventional double aluminum packaging.
The technical scheme adopted by the invention has the beneficial effects that:
1. the problems of fluidization delamination and vibration delamination can not be caused, the potential risk of content uniformity is very small, the process is stable, and the durability is good.
2. Not easy to absorb moisture, good appearance and better stability. The bilastine orally disintegrating tablet prepared by the prescription process of the invention is not easy to absorb moisture under high humidity condition, has no obvious change in disintegration time limit after long-term storage, does not generate black spots under high temperature condition, and has higher stability than the original preparation.
3. Has good taste, and has refreshing and fine and smooth taste without gravel after disintegration.
Drawings
FIG. 1 is a microscope image of plate-like mannitol and globular mannitol;
figure 2 is a lifting disintegrating instrument hanging basket structure.
Detailed description of the invention
The following are specific embodiments of the present invention, which are intended to further illustrate the invention and not to limit it.
The following examples are experimental methods without specifying specific conditions, and generally follow the methods known in the art. The test materials used in the following examples were purchased from a conventional biochemical reagent store unless otherwise specified.
The method for measuring the particle size of the mannitol used in the method is as follows: according to the particle size and particle size distribution determination method (third method of 0982 in the four ministry of pharmacopoeia 2015 edition of China) (SYMPA HELOS/RODOS/M or laser particle size analyzer with equivalent performance), about 1.5g of mannitol is taken, the light shielding rate of a detector is within the range of 5% -15%, the dry method determination is carried out according to the method, the dispersion pressure is 2.0bar, the vibration speed is 50%, and the average value of 3 continuous measurements is taken. The mannitol granules of different types of mannitol used in the present invention have the particle size and properties shown in table 1.
TABLE 1 particle size and Properties of mannitol particles of different types
The mannitol microscopic shape determination method is as follows: adopting a NSZ608T microscope, taking a proper amount of mannitol, adjusting the microscope to make the object image clear, and taking the following characteristic images, as shown in figure 1, the left graph shows the sheet mannitol, and the right graph shows the spherical mannitol.
Comparative example 1 original preparation
The common name is: bilastine orally disintegrating tablet
The name of English: bilastine Orally distinguishing tables
Trade name: opexa
Specification: 10mg of
The certificate holder: menarini International Operations Luxembourg S.A.
The manufacturer: menarini Manufacturing logics and Services s.r.l.
Comparative example 2
A batch of samples was prepared according to patent CN104398481A, example 3, and the recipe was as shown in table 2 below:
table 2 CN104398481A formula of example 3
| Composition of | Content of unit preparation |
| Bilastine | 30mg |
| Microcrystalline cellulose | 60mg |
| Lactose | 37.5mg |
| Polyvinylpyrrolidone K30 | 7.5mg |
| Crosslinked polyvinylpyrrolidone | 12mg |
| Colloidal silicon dioxide | 0.75mg |
| Magnesium stearate | 0.75mg |
The process comprises the following steps:
(1) the bilastine raw material medicine, microcrystalline cellulose, lactose, polyvinylpyrrolidone K30, cross-linked polyvinylpyrrolidone and silicon dioxide are respectively sieved by a 100-mesh sieve.
(2) Weighing the materials in the step (1) according to the prescription amount, and then uniformly mixing.
(3) And (3) carrying out dry granulation on the mixed powder obtained in the step (2), and sieving the powder by using a 18-mesh sieve.
(4) The dry granules are mixed well with the prescribed amount of magnesium stearate.
(5)8mm round punched piece, the hardness is controlled to 3-6 kgf.
(6) And (7) packaging with double aluminum.
Examples 1 to 6
The formulations of examples 1-6 are shown in Table 3:
TABLE 3 formulations of examples 1-6
In Table 3, the mannitol used in example 1 was mannitol 160C produced by Rogatte, France, the mannitol used in example 2 was mannitol Granutol F produced by Funredt, Japan, and the mannitol used in example 3 was mannitol Grautol F produced by Funredt, JapanThe mannitol of (1) is mannitol 25C produced by Rogat, the mannitol used in example 4 is mannitol 50C produced by Rogat (the particle size of the mannitol of examples 1-4 is shown in Table 1), the mannitol used in example 5 is mannitol 160C produced by Rogat, the particle size is controlled to 48.86 μm < D50＜62.91μm、115.92μm＜D90< 134.72 μm; example 6 mannitol Powder manufactured by SPI corporation in America with particle size controlled at 48.86 μm < D50＜62.91μm、115.92μm＜D90< 134.72 μm. The pulverized mannitol was confirmed to be in a flake form by a microscope.
Procedure for examples 1-6:
(1) hydroxypropyl methylcellulose in the prescription amount is weighed and added into a proper amount of purified water to prepare a bonding agent solution.
(2) Weighing and uniformly mixing the bilastine bulk drug, mannitol, croscarmellose sodium and sucralose according to the formula amount.
(3) And (3) carrying out wet granulation, drying and granule finishing on the mixed powder in the step (2) by adopting a prepared adhesive solution to obtain dry granules.
(4) Adding the sodium stearyl fumarate into the dry granules according to the prescription amount, and uniformly mixing.
(5)8mm round punched piece, the hardness is controlled to 3-6 kgf.
(6) And (7) packaging with double aluminum.
Example 7 quality evaluation
1. The content uniformity detection method comprises the following steps: taking 10 tablets of the comparative example and the example respectively, placing 10 tablets in 10 measuring flasks respectively, adding a solvent to dissolve and dilute the main drug to prepare a test solution containing about 0.5mg of bilastine in each 1ml, injecting into a high performance liquid chromatograph, and recording a chromatogram; a control solution containing about 0.5mg of bilastine per 1ml is prepared by the same method, and the relative content of each single dose, which is marked as 100%, is calculated according to an external standard method by peak area.
2. The moisture absorption weight gain detection method comprises the following steps: taking 10 tablets of the comparative example and the example, precisely weighing the tablets to obtain m1, placing the tablets in an environment of RH 90% +/-5% for 10 days, precisely weighing the tablets to obtain m2, and calculating the weight gain percentage to be
3. The disintegration time limit detection method comprises the following steps: taking 6 pieces of the product, respectively placing in the glass tubes of the above hanging baskets (see figure 2 for instrument device), hanging the hanging baskets on a support through a stainless steel shaft at the upper end, immersing in a 1000ml beaker, adjusting the position of the hanging baskets to enable the screen to be 25mm away from the bottom of the beaker when the hanging baskets are lowered to a low point, filling water with the temperature of 37 +/-1 ℃ in the beaker, adjusting the height of the water level to enable the screen to be 15mm below the water surface when the hanging baskets are raised to a high point, and enabling the tops of the hanging baskets not to be immersed in the solution. Starting the disintegration tester to check, and observing the time required by the sample to be totally disintegrated and dissolved or to be crushed.
4. The experimental results are as follows:
as shown in Table 4, the formula of the disintegrating tablet disclosed by the application has the advantages that the obtained finished product is not easy to absorb moisture in the storage process, black spots cannot be generated under a high-temperature condition, the disintegration is rapid, and the mouth feel is cool and slightly sweet.
And mannitol in tablet form is used, and particle size is controlled to 48.86 μm < D50＜62.91μm、115.92μm＜D90Less than 134.72 μm, and specifically, mannitol 50C (flake) produced by Rogaite or mannitol in other types of flakes obtained by pulverizing can be used to obtain better uniformity, such as example 4, example 5 and example 6, wherein the content uniformity is very uniform, and the variation ranges are 99.3% -100.8%, 98.8% -100.6% and 99.0% -101.1%, which are smaller than the variation ranges of the commercially available preparation and the patented products.
And the content uniformity of the obtained finished product is within the range of 95.5-102.8% by adopting the flaky mannitol 160C with slightly larger particle size. The mannitol 25C in a flake shape with a slightly smaller particle size is adopted, the content uniformity of the finished product is within a variation range of 96.5-105.5%, and the variation range is larger. By adopting the spherical mannitol Grautol F with the same particle size, the content uniformity of the obtained finished product also has a very large variation range of 93.5-107.5%.
It can be seen from this that: the technical effect of the invention which is realized by adopting the flaky mannitol and controlling the granularity within a certain range cannot be reasonably expected, is not obvious to a person skilled in the art, and has outstanding substantive features and remarkable progress.
TABLE 4 quality evaluation
Claims (10)
1. The bilastine orally disintegrating tablet is characterized by comprising the following components in parts by weight:
2. the bilastine orally disintegrating tablet of claim 1, wherein said mannitol microstructure is in the form of a flake or sphere.
3. The bilastine orally disintegrating tablet of claim 2, wherein said mannitol microstructure is in the form of a tablet.
4. The bilastine orally disintegrating tablet of claim 2, wherein the mannitol particle size is controlled to 30 μm < D50＜90μm、65μm＜D90＜205μm。
5. The bilastine orally disintegrating tablet according to claim 2, wherein said mannitol is in a tablet form, and the particle size is controlled to be 48 μm < D50＜63μm、115μm＜D90＜135μm。
6. The method for preparing bilastine orally disintegrating tablets according to any one of claims 1 to 5, comprising the steps of:
(1) the hydroxypropyl methylcellulose in the prescription amount is prepared into a solution for later use;
(2) uniformly mixing the bilastine, the mannitol, the croscarmellose sodium and the sucralose according to the prescription amount;
(3) wet granulating, drying and grading the mixed powder prepared in the step (2) by adopting the solution prepared in the step (1) to obtain dry granules;
(4) adding sodium stearyl fumarate with a prescription amount into the dry granules, and uniformly mixing to obtain intermediate granules;
(5) and (4) tabletting the intermediate granules obtained in the step (4).
7. The preparation method according to claim 6, wherein the hydroxypropyl methylcellulose in the prescription in the step (1) is prepared into a solution with a mass concentration of 3-7%.
8. The method according to claim 6, wherein the pellet of step (5) is formed by using an 8mm round punch.
9. The production method according to claim 6, wherein the tablet hardness in the step (5) is controlled to 3 to 6 kgf.
10. Use of the bilastine orally disintegrating tablet according to any one of claims 1 to 5 as a medicament for the treatment of symptomatic rhinitis and urticaria.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040058896A1 (en) * | 2000-12-07 | 2004-03-25 | Rango Dietrich | Pharmaceutical preparation comprising an active dispersed on a matrix |
| CN103655497A (en) * | 2013-12-18 | 2014-03-26 | 北京华禧联合科技发展有限公司 | Montelukast orally disintegrating tablet and preparation method thereof |
| CN104398481A (en) * | 2014-10-29 | 2015-03-11 | 万全万特制药江苏有限公司 | Bilastine orally disintegrating tablet and preparing method thereof |
| CN106727345A (en) * | 2015-11-20 | 2017-05-31 | 江苏正大丰海制药有限公司 | A kind of pharmaceutical composition of montelukast sodium |
-
2021
- 2021-09-28 CN CN202111147024.6A patent/CN113662920A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040058896A1 (en) * | 2000-12-07 | 2004-03-25 | Rango Dietrich | Pharmaceutical preparation comprising an active dispersed on a matrix |
| CN103655497A (en) * | 2013-12-18 | 2014-03-26 | 北京华禧联合科技发展有限公司 | Montelukast orally disintegrating tablet and preparation method thereof |
| CN104398481A (en) * | 2014-10-29 | 2015-03-11 | 万全万特制药江苏有限公司 | Bilastine orally disintegrating tablet and preparing method thereof |
| CN106727345A (en) * | 2015-11-20 | 2017-05-31 | 江苏正大丰海制药有限公司 | A kind of pharmaceutical composition of montelukast sodium |
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